CD19-Directed CAR-T Cell Therapy in Refractory Systemic Lupus Erythematosus (CLEVER-SLE)

CD19-targeted Lymphocyte Engineering Validation for the trEatment of Refractory Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease in which the immune system mistakenly attacks the body's own tissues and organs. The disease can affect the skin, joints, kidneys, blood cells, brain, and other organs, leading to significant health problems and reduced quality of life. Although several treatments are available, some patients continue to have active disease despite receiving standard therapies.

Recent research has shown that B cells, a type of immune cell, play a central role in the development and persistence of SLE. CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an innovative treatment that uses a patient's own immune cells, genetically modified to recognize and eliminate B cells. This approach has already shown remarkable success in certain blood cancers and has recently produced encouraging results in patients with severe autoimmune diseases, including SLE.

The CLEVER-SLE study is a Phase I/II clinical trial designed to evaluate the safety and potential effectiveness of CD19-directed CAR-T cell therapy produced at Ribeirao Preto Blood Bank in patients with SLE who have not responded adequately to conventional treatments. Participants will undergo the collection of their own immune cells, which will be modified in a specialized laboratory to produce CAR-T cells. After receiving preparatory chemotherapy, participants will receive a single intravenous infusion of these CAR-T cells.

The main goal of this study is to evaluate the safety of this treatment. Researchers will also assess its effects on disease activity, symptoms, organ involvement, medication requirements, immune system markers, and the duration of clinical responses. The study aims to determine whether CD19-directed CAR-T cell therapy can provide a new treatment option for patients with refractory SLE and contribute to the development of CAR-T therapies for autoimmune diseases.

Study Overview

• Status: Not yet recruiting
• Conditions: Lupus Erythematosus, Systemic
• Intervention / Treatment: Biological: Autologous CD19-Directed CAR-T Cells Manufactured at Ribeirão Preto Blood Center

Detailed Description

Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by loss of immune tolerance, production of pathogenic autoantibodies, and immune-mediated tissue injury. The disease can affect virtually any organ system, including the skin, joints, kidneys, hematologic system, cardiovascular system, and central nervous system. Despite major advances in the understanding of disease pathogenesis and the availability of immunosuppressive and biologic therapies, many patients continue to experience persistent disease activity, recurrent flares, progressive organ damage, reduced quality of life, and increased mortality.

B lymphocytes play a central role in the pathogenesis of SLE. Beyond their ability to differentiate into antibody-producing plasma cells, B cells contribute to disease development through antigen presentation, cytokine production, and maintenance of autoreactive immune responses. The persistence of autoreactive B-cell populations is believed to be a key driver of chronic disease activity and treatment resistance.

Several therapeutic strategies targeting B cells have been developed for SLE, including anti-CD20 monoclonal antibodies and inhibitors of B-cell survival pathways. Although these approaches have improved outcomes for many patients, a substantial proportion of individuals fail to achieve sustained remission. One potential limitation of antibody-based therapies is their inability to completely eliminate autoreactive B-cell populations residing within inflamed tissues and specialized immune niches. In contrast, CD19-directed CAR-T cells are living immune effectors capable of expanding in vivo, trafficking to affected tissues, and mediating deep depletion of B cells not only in the peripheral blood but also within sites of ongoing autoimmune inflammation. This broader and more profound tissue-level B-cell depletion may contribute to more durable disease control and potentially restore immune tolerance. In addition, existing therapies often require continuous administration and may be associated with cumulative toxicities, incomplete disease control, or relapse after treatment discontinuation.

CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy represents a novel therapeutic strategy that enables a patient's own T lymphocytes to recognize and eliminate CD19-expressing B cells. This approach has demonstrated unprecedented efficacy in B-cell malignancies and has transformed the treatment landscape of several hematologic cancers. More recently, emerging clinical evidence has suggested that deep B-cell depletion induced by CD19-directed CAR-T cells may also be capable of resetting abnormal immune responses in autoimmune diseases.

Early clinical experiences in patients with severe refractory autoimmune diseases, including systemic lupus erythematosus, have reported rapid and profound reductions in disease activity, sustained clinical remissions, normalization of serological markers, and significant reductions in the need for immunosuppressive medications. These findings have generated considerable interest in the potential application of CAR-T cell therapy beyond oncology and have established a strong scientific rationale for further investigation in autoimmune disorders.

The CAR-T product evaluated in this study consists of autologous T lymphocytes genetically modified to express a chimeric antigen receptor directed against CD19. The product is manufactured at the Ribeirão Preto Blood Center (Hemocentro de Ribeirão Preto), one of the leading academic cell therapy centers in Brazil. This manufacturing platform has previously demonstrated feasibility, safety, and clinical activity in patients with hematologic malignancies and serves as the foundation for the present investigation.

The CLEVER-SLE study was developed to evaluate the use of CD19-directed CAR-T cell therapy manufactured at the Ribeirão Preto Blood Center in patients with refractory systemic lupus erythematosus. The study seeks to expand current knowledge regarding the safety profile and therapeutic potential of CAR-T cells in autoimmune diseases while generating clinical evidence to support the development of advanced cellular therapies for patients with severe disease who have limited treatment options.

By investigating a strategy capable of directly targeting the cellular drivers of autoimmunity, this study aims to contribute to the development of transformative therapies that may achieve sustained disease control and improve long-term outcomes for patients with refractory SLE.

• Study Type: Interventional
• Enrollment (Estimated): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Diego V. Clé, MD, MBA, PhD; Phone Number: +55 16 21019300; Email: terapia@hemocentro.fmrp.usp.br
• Study Contact Backup: Name: Maria Carolina Oliveira Rodrigues, MD, PhD; Email: mcarolor@usp.br

Study Locations

• Brazil
  • São Paulo
    • Ribeirão Preto, São Paulo, Brazil, 14048-900
      • Hospital das Clinicas de Ribeirão Preto (HCFMRP-USP)
      • Contact: Diego V. Clé, MD, MBA, PhD; Phone Number: +55 16 21019300; Email: terapia@hemocentro.fmrp.usp.br
      • Contact: Maria Carolina Oliveira Rodrigues, MD, PhD; Email: mcarolor@usp.br
    • São Paulo, São Paulo, Brazil, 05403-010
      • Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP)
      • Contact: Eloisa Bonfá, Full Professor; Phone Number: +55 11 30617492; Email: eloisa.bonfa@hc.fm.usp.br
      • Contact: Luciana Seguro, MD, PhD; Email: luciana.seguro@hc.fm.usp.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adults aged 18 to 50 years, inclusive.
• Diagnosis of systemic lupus erythematosus (SLE) according to the 2019 ACR/EULAR classification criteria.
• Active disease at screening, defined as SLEDAI-2K ≥4 and Physician Global Assessment (PGA) ≥0.5.
• Inadequate response, intolerance, or contraindication to corticosteroids and at least two of the following therapies: azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, belimumab, rituximab, or tacrolimus.

• Adequate organ function, including:

  • Hepatic function: AST and ALT ≤3× upper limit of normal (ULN); total bilirubin ≤2× ULN (participants with documented Gilbert syndrome are eligible).
  • Hematologic function: neutrophils ≥1,000/mm³; hemoglobin ≥8 g/dL without transfusion within 14 days; lymphocytes ≥500/mm³; platelets ≥20,000/mm³ without transfusion within 14 days.
  • Renal function: estimated creatinine clearance ≥30 mL/min (CKD-EPI).
  • Cardiac function: left ventricular ejection fraction ≥40%.
  • Pulmonary function: oxygen saturation ≥92% on room air.
• Women of childbearing potential must agree to use highly effective contraception during study participation and for 12 months after CAR-T cell infusion.
• Male participants must agree to use barrier contraception during study participation and for 12 months after CAR-T cell infusion.
• Ability to understand and provide written informed consent.

Exclusion Criteria:

• Severe pulmonary hypertension (estimated pulmonary artery systolic pressure >50 mmHg).
• Requirement for systemic anticoagulation at screening.
• Clinically significant cardiovascular disease, including NYHA Class III/IV heart failure, myocardial infarction, unstable arrhythmias, or unstable angina within the previous 6 months.
• Active neurological disease (stroke, epilepsy, or neurodegenerative disorders) within the previous 12 months.
• History of malignancy within 2 years prior to screening, except for adequately treated non-melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer, ductal carcinoma in situ of the breast, or stage I uterine cancer.
• Previous or suspected hemophagocytic lymphohistiocytosis/macrophage activation syndrome.
• Active or uncontrolled bacterial, viral, fungal, or other infection.
• Active hepatitis B infection or detectable HBV DNA.
• Active hepatitis C infection or detectable HCV RNA.
• Human immunodeficiency virus (HIV) infection.
• Pregnancy, breastfeeding, or plans to become pregnant during the study or within 12 months after CAR-T cell infusion.
• Major surgery within 4 weeks prior to screening.
• Administration of a live attenuated vaccine within 4 weeks prior to screening.
• Prior allogeneic or autologous hematopoietic stem cell transplantation or prior solid organ transplantation.
• Inability or unwillingness to comply with study procedures and follow-up requirements.
• Any medical condition that, in the investigator's judgment, could compromise participant safety or interfere with study assessments.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Autologous CD19-Directed CAR-T Cells; Participants with refractory systemic lupus erythematosus will undergo leukapheresis for the manufacture of autologous CD19-directed CAR-T cells, followed by lymphodepleting chemotherapy and a single intravenous infusion of the CAR-T cell product.

Biological: Autologous CD19-Directed CAR-T Cells Manufactured at Ribeirão Preto Blood Center; Autologous CD19-directed chimeric antigen receptor T (CAR-T) cells developed and manufactured at the Ribeirão Preto Blood Center (Hemocentro de Ribeirão Preto, Brazil). T lymphocytes collected by leukapheresis are genetically modified ex vivo using a lentiviral vector to express a CD19-specific chimeric antigen receptor and subsequently expanded under Good Manufacturing Practice (GMP) conditions. Following standard lymphodepleting chemotherapy, participants receive a single intravenous infusion of the autologous CAR-T cell product. The therapy is intended to achieve deep and sustained depletion of CD19-positive B cells implicated in the pathogenesis of systemic lupus erythematosus.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence and Severity of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)	Incidence and maximum grade of CRS and ICANS following infusion of autologous CD19-directed CAR-T cells, assessed according to ASTCT consensus criteria.	30 days after CAR-T cell infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Grade ≥3 Cytopenias	Incidence of grade ≥3 anemia, neutropenia, lymphopenia, and thrombocytopenia according to CTCAE v6.0.	Up to 90 days after CAR-T cell infusion
Time to Hematologic Recovery	Time to resolution of cytopenias to grade <1.	Up to 12 months after CAR-T cell infusion
Incidence and Severity of Infections	Cumulative incidence and severity of infections	Up to 12 months after CAR-T cell infusion
Incidence of Serious Infections	Incidence of grade ≥3 infections according to CTCAE v6.0	Up to 12 months after CAR-T cell infusion
Changes in Serum Immunoglobulin Levels	Absolute and relative changes in serum IgG, IgA, and IgM concentrations compared with baseline	Baseline, Day 30, Day 90, Day 180, and Day 360
Incidence of Other CAR-T Cell-Associated Toxicities	Incidence and severity of coagulopathy, immune effector cell-associated hemophagocytic syndrome (IEC-HS), cytomegalovirus reactivation, and local immune effector cell-associated toxicity syndrome (LICATS)	Up to 12 months after CAR-T cell infusion
Deep Remission Rate	Percentage of participants achieving deep remission, defined as clinical SLEDAI-2K=0 (allowing isolated serological activity), Physician Global Assessment (PGA) ≤0.5, and no requirement for additional immunosuppressants, biologics, small molecules, or corticosteroids after CAR-T cell therapy.	6 months after CAR-T cell infusion
SRI-4 Response Rate	Percentage of participants achieving an SRI-4 response, defined as a ≥4-point reduction in SLEDAI-2K score, no new BILAG A score and no more than one new BILAG B score, and no worsening in PGA (increase <0.3 points)	6 months after CAR-T cell infusion
Lupus Low Disease Activity State (LLDAS) Achievement Rate	Percentage of participants achieving LLDAS criteria	6 and 12 months after CAR-T cell infusion
DORIS Remission Rate	Percentage of participants achieving Definitions Of Remission In SLE (DORIS) criteria	6 and 12 months after CAR-T cell infusion
Renal Response Rate	Among participants with active lupus nephritis (proteinuria ≥500 mg/24 hours at baseline), percentage achieving complete renal response or partial renal response	6 and 12 months after CAR-T cell infusion
Cutaneous Lupus Response Rate	Among participants with baseline CLASI-Activity score ≥10, percentage achieving CLASI-50 response, defined as ≥50% reduction in CLASI-Activity score from baseline.	6 and 12 months after CAR-T cell infusion
Articular Response Rate	Among participants with ≥6 active arthritic joints at baseline, percentage achieving at least 50% reduction in the number of active joints	6 and 12 months after CAR-T cell infusion
Anti-dsDNA Serologic Response	Percentage of participants achieving negative anti-double-stranded DNA antibody titers (negative or ≤1:10)	6 and 12 months after CAR-T cell infusion
Corticosteroid and Immunosuppressant-Free Remission	Percentage of participants not receiving corticosteroids or immunosuppressive medications	6 and 12 months after CAR-T cell infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lymphocyte Subpopulation Kinetics	Longitudinal assessment of B-cell, T-cell, and NK-cell populations in peripheral blood following CD19-directed CAR-T cell therapy	Screening, pre-lymphodepletion, Day 0, Day 7, Day 17, Day 24, Day 30, Day 60, Day 90, Day 180, and Day 360
CAR-T Cell Expansion, Persistence, and Immunophenotype	Assessment of circulating CAR-T cell levels and immunophenotypic characteristics following infusion	Pre-lymphodepletion, Day 3, Day 7, Day 10, Day 17, Day 24, Day 30, Day 60, Day 90, Day 180, and Day 360
Inflammatory Cytokine Kinetics	Longitudinal assessment of circulating inflammatory cytokine levels	Pre-lymphodepletion, Day 3, Day 7, Day 10, Day 17, Day 24, Day 30, Day 60, Day 90, Day 180, and Day 360
Complement Recovery Kinetics	Changes in serum complement C3 and C4 levels following treatment	Screening, pre-lymphodepletion, Day 30, Day 60, Day 90, Day 180, and Day 360
Vaccine Antibody Titers	Changes in antibody titers against measles and diphtheria-tetanus vaccination antigens	Pre-lymphodepletion, Day 30, Day 60, Day 90, Day 180, and Day 360
NETosis Biomarkers	Changes in peripheral blood markers associated with neutrophil extracellular trap (NET) formation and NETosis	Screening, Day 30, Day 60, Day 90, Day 180, and Day 360

Collaborators and Investigators

• Sponsor: University of Sao Paulo
• Collaborators: Regional Blood Center of Ribeirao Preto

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: June 15, 2026
• First Submitted That Met QC Criteria: June 15, 2026
• First Posted (Actual): June 22, 2026

Study Record Updates

• Last Update Posted (Actual): June 22, 2026
• Last Update Submitted That Met QC Criteria: June 15, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: SLE; Systemic Lupus Erythematosus; Autoimmune Diseases; CD19; Immune Reconstitution; Lupus Nephritis; Cellular Therapy; CAR-T Cell Therapy; Refractory Systemic Lupus Erythematosus; Chimeric Antigen Receptor T Cells; B Lymphocytes; Advanced Therapy Medicinal Products; CD19-Directed CAR-T Cells; B Cell Depletion; Autologous CAR-T Cells
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Connective Tissue Diseases; Immune System Diseases; Glomerulonephritis; Nephritis; Skin and Connective Tissue Diseases; Lupus Erythematosus, Systemic; Lupus Nephritis; Autoimmune Diseases
• Other Study ID Numbers: HEMO-03-CART

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No